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Chapter 41 : Mechanisms of Defense against Intracellular Pathogens Mediated by Human Macrophages

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Abstract:

While animal models of human disease have provided great insights that would have been difficult to achieve in studies in humans, our initial experiments on protection against were designed to take advantage of transgenic knockout mice. While animal models have contributed enormously to our understanding, it must be noted that none faithfully reproduces the pathology or course of disease of human tuberculosis (TB) or leprosy. With that caveat, we explored the question of immunologically necessary conditions for protection of mice against infection. We found that mice lacking the gene for gamma interferon (IFN-γ) died from challenge in a matter of 2 to 3 weeks after intravenous challenge and within a month after aerosol challenge ( ). We hypothesized that the pathology observed in the lungs would likely be mediated by local production of tumor necrosis factor alpha (TNF-α) and were quite surprised to learn that TNF-α-depleted mice succumbed with precisely the same time to death as the IFN-γ knockouts ( ). Additionally, we ( ) and others ( ) found that mice whose major histocompatibility complex (MHC) class I presentation to cytotoxic T lymphocytes (CTLs) was deficient, e.g., β-microglobulin deficient or TAP (transporter associated with antigen processing) deficient, succumbed to TB infection far earlier than control mice, but many weeks later than the IFN-γ- and TNF-α-deficient mice ( ) ( Fig. 1 ). These results established that IFN-γ and TNF-α are necessary for initial protection in mice, likely mediated by innate immunity and cytokine-activated macrophages, and suggested that CTLs may play a role later in infection.

Citation: Bloom B, Modlin R. 2017. Mechanisms of Defense against Intracellular Pathogens Mediated by Human Macrophages, p 727-738. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0006-2015
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Figure 1

Necessary conditions for protection in mice. Depletion of IFN-γ , TNF-α , or MHC class I results in increased susceptibility and death following challenge in C57BL/6 mice. B2M, beta-2 microglobulin; BCG, Bacillus Calmette–Guérin; GKO, IFN-gamma gene knock out; WT, wild type. Sources: references .

Citation: Bloom B, Modlin R. 2017. Mechanisms of Defense against Intracellular Pathogens Mediated by Human Macrophages, p 727-738. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0006-2015
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Figure 2

Macrophages in leprosy lesions. Cellular infiltrates in tuberculoid and lepromatous leprosy lesions. The third panel shows an acid-fast stain, indicating the abundance of bacilli in lepromatous lesions. Courtesy of Thomas H. Rea.

Citation: Bloom B, Modlin R. 2017. Mechanisms of Defense against Intracellular Pathogens Mediated by Human Macrophages, p 727-738. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0006-2015
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Figure 3

Inducible NOS2 (iNOS) is essential for killing of by activated mouse macrophages but not for human monocyte-derived macrophages. L-NIL is an inhibitor of NOS2. Source: reference .

Citation: Bloom B, Modlin R. 2017. Mechanisms of Defense against Intracellular Pathogens Mediated by Human Macrophages, p 727-738. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0006-2015
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Figure 4

TLR2-activated human monocyte-derived macrophages are able to kill , whereas activated DCs (derived by culture of monocytes with GM-CSF and IL-4) were unable to kill under the same conditions. ** ≤ 0.01. Source: reference .

Citation: Bloom B, Modlin R. 2017. Mechanisms of Defense against Intracellular Pathogens Mediated by Human Macrophages, p 727-738. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0006-2015
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Figure 5

Failure of TLR2-activated human macrophages to induce cathelicidin (Cath.) mRNA in culture with sera from African Americans can be reversed by addition of 25-hydroxyvitamin D. IFN-γ activates human macrophages to produce cathelicidin to a comparable extent as the innate response to TLR2 agonists. Production of cathelicidin mRNA is dependent on vitamin D and inhibited by VAZ, a VDR antagonist. Vitamin D is essential for human macrophages activated by either TLR2 or IFN-γ to kill . FC, fold change. Sources: references .

Citation: Bloom B, Modlin R. 2017. Mechanisms of Defense against Intracellular Pathogens Mediated by Human Macrophages, p 727-738. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0006-2015
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Figure 6

Inhibition of the effect of IFN-γ in stimulating induction of cathelicidin (Cath) mRNA by IFN-β is mediated by IL-10. FC, fold change. * ≤ 0.05. Source: reference .

Citation: Bloom B, Modlin R. 2017. Mechanisms of Defense against Intracellular Pathogens Mediated by Human Macrophages, p 727-738. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0006-2015
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Figure 7

Common activation pathway for human macrophages stimulated through the innate receptor TLR2 or the acquired immune activator IFN-γ. IFN-β suppresses that activation through IL-10 by inhibiting induction of both CYP27B1 and the VDR. Source: reference .

Citation: Bloom B, Modlin R. 2017. Mechanisms of Defense against Intracellular Pathogens Mediated by Human Macrophages, p 727-738. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0006-2015
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Figure 8

IL-15 defense response network links IL-32 to the vitamin D antimicrobial pathway. The IL-15-induced host defense network reveals IL-32 as a hub gene, connected to sets of genes involved in host defense, including the vitamin D antimicrobial pathway. The color of each node depicts fold change (FC) induction by IL-15 at 24 h. Source: reference .

Citation: Bloom B, Modlin R. 2017. Mechanisms of Defense against Intracellular Pathogens Mediated by Human Macrophages, p 727-738. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0006-2015
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